A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis.

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10-8): rs781716 (P = 4.71 × 10-9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10-8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10-9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10-8, OR = 0.45; P = 3.31 × 10-8, OR = 0.45; P = 1.09 × 10-8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10-8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10-6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821-55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

UC Care Check-A Postoperative Neurosurgery Operating Room Checklist: An Interrupted Time Series Study.

BACKGROUND: The effectiveness of neurosurgical operating room (OR) checklists to improve communication, safety attitudes, and clinical outcomes is uncertain. PURPOSE: To develop, implement, and evaluate a post-operative neurosurgery operating room checklist. METHODS: Four large academic medical centers participated in this study. We developed an evidence-based checklist to be performed at the end of every adult-planned or emergent surgery in which all team members pause to discuss key elements of the case. We used a prospective interrupted time series study design to assess trends in clinical and cost outcomes. Safety attitudes and communication among OR providers were also assessed. RESULTS: There were 11,447 neurosurgical patients in the preintervention and 10,973 in the postintervention periods. After implementation, survey respondents perceived that postoperative checklists were regularly performed, important issues were communicated at the end of each case, and patient safety was consistently reinforced. Observed to expected (O/E) overall mortality rates remained less than one, and 30-day readmission rate, length of stay index, direct cost index, and perioperative venous thromboembolism and hematoma rates remained unchanged as a result of checklist implementation. CONCLUSION: A neurosurgical checklist can improve OR team communication; however, improvements in safety attitudes, clinical outcomes, and health system costs were not observed.

Real-time augmented reality for delineation of surgical margins during neurosurgery using autofluorescence lifetime contrast.

Current clinical brain imaging techniques used for surgical planning of tumor resection lack intraoperative and real-time feedback; hence surgeons ultimately rely on subjective evaluation to identify tumor areas and margins. We report a fluorescence lifetime imaging (FLIm) instrument (excitation: 355 nm; emission spectral bands: 390/40 nm, 470/28 nm, 542/50 nm and 629/53 nm) that integrates with surgical microscopes to provide real-time intraoperative augmentation of the surgical field of view with fluorescent derived parameters encoding diagnostic information. We show the functionality and safety features of this instrument during neurosurgical procedures in patients undergoing craniotomy for the resection of brain tumors and/or tissue with radiation damage. We demonstrate in three case studies the ability of this instrument to resolve distinct tissue types and pathology including cortex, white matter, tumor and radiation-induced necrosis. In particular, two patients with effects of radiation-induced necrosis exhibited longer fluorescence lifetimes and increased optical redox ratio on the necrotic tissue with respect to non-affected cortex, and an oligodendroglioma resected from a third patient reported shorter fluorescence lifetime and a decrease in optical redox ratio than the surrounding white matter. These results encourage the use of FLIm as a label-free and non-invasive intraoperative tool for neurosurgical guidance.

The Impact of Unmet Communication and Education Needs on Neurosurgical Patient and Caregiver Experiences of Care: A Qualitative Exploratory Analysis.

OBJECTIVE: To describe neurosurgical patient and caregiver perceptions of provider communication, the impact of patient education, and their understanding of information given to them throughout the neurosurgical care trajectory. METHODS: We organized focus groups composed of patients who had been hospitalized on the neurosurgical service at 5 urban academic tertiary referral hospitals within a large university health system, along with the patients' caregivers. During focus groups, we used semistructured questions to answer the study questions. Content analysis was used to analyze the data. RESULTS: Forty-three patients and caregivers took part in 5 focus groups. In total we identified 12 coding categories (or topics) that were associated with patient and family information needs. Despite the fact all patients were receiving care within the same health system, often with the same care team and clinical environments, their experiences often could not have been more different. We found stark variations in how patients and caregivers described the quality of communication and patient education they received that affected their satisfaction. Satisfied patients and caregivers generally felt well informed and reported good understanding of the clinical care plan throughout the perioperative course, whereas dissatisfied patients struggled with unanswered questions, unmet information needs, and a sense of confusion throughout their care experience. CONCLUSIONS: Our study describes several unmet needs, finds inconsistencies in how information is delivered and a lack of patient-centered and caregiver-centered approaches to communication. Neurosurgery groups should identify unmet needs at their institution and implement strategies and interventions to improve the patient and caregiver experience.

Ventriculoperitoneal shunt infection with Mycobacterium fortuitum: a rare offending organism.

Postsurgical infection is one of the greatest potential morbidities of ventriculoperitoneal shunt surgery. The majority of infections can be linked to contamination with skin flora at the time of surgery, a phenomenon that has been well described. However, there is a paucity of literature regarding infection with nontuberculous mycobacteria. The authors report a case of postoperative ventriculoperitoneal shunt infection with Mycobacterium fortuitum and review the available neurosurgical literature and treatment strategies.

Intracerebroventricular opiate infusion for refractory head and facial pain.

AIM: To study the risks and benefits of intracerebroventricular (ICV) opiate pumps for the management of benign head and face pain. METHODS: SSix patients with refractory trigeminal neuralgia and/or cluster headaches were evaluated for implantation of an ICV opiate infusion pump using either ICV injections through an Ommaya reservoir or external ventricular drain. Four patients received morphine ICV pumps and two patientS received a hydromorphone pump. Of the Four patients with morphine ICV pumps, one patient had the medication changed to hydromorphone. Preoperative and post-operative visual analog scores (VAS) were obtained. Patients were evaluated post-operatively for a minimum of 3 mo and the pump dosage was adjusted at each outpatient clinic visit according to the patient's pain level. RESULTS: All 6 patients had an intracerebroventricular opiate injection trial period, using either an Ommaya reservoir or an external ventricular drain. There was an average VAS improvement of 75.8%. During the trial period, no complications were observed. Pump implantation was performed an average of 3.7 wk (range 1-7) after the trial injections. After implantation, an average of 20.7 ± 8.3 dose adjustments were made over 3-56 mo after surgery to achieve maximal pain relief. At the most recent follow-up (26.2 mo, range 3-56), VAS scores significantly improved from an average of 7.8 ± 0.5 (range 6-10) to 2.8 ± 0.7 (range 0-5) at the final dose (mean improvement 5.0 ± 1.0, P < 0.001). All patients required a stepwise increase in opiate infusion rates to achieve maximal benefit. The most common complications were nausea and drowsiness, both of which resolved with pump adjustments. On average, infusion pumps were replaced every 4-5 years. CONCLUSION: These results suggest that ICV delivery of opiates may potentially be a viable treatment option for patients with intractable pain from trigeminal neuralgia or cluster headache.

A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9.

Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one in 5,000 newborns. We conducted, to our knowledge, the first genome-wide association study for nonsyndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic case-parent trios of European ancestry (NHW). We found robust associations in a 120-kb region downstream of BMP2 flanked by rs1884302 (P = 1.13 × 10(-14), odds ratio (OR) = 4.58) and rs6140226 (P = 3.40 × 10(-11), OR = 0.24) and within a 167-kb region of BBS9 between rs10262453 (P = 1.61 × 10(-10), OR = 0.19) and rs17724206 (P = 1.50 × 10(-8), OR = 0.22). We replicated the associations to both loci (rs1884302, P = 4.39 × 10(-31) and rs10262453, P = 3.50 × 10(-14)) in an independent NHW population of 172 unrelated probands with sNSC and 548 controls. Both BMP2 and BBS9 are genes with roles in skeletal development that warrant functional studies to further understand the etiology of sNSC.

Breast-related CSF shunt complications: literature review with illustrative case.

In this article, we discuss and classify breast-related ventriculoperitoneal (VP) cerebrospinal fluid (CSF) shunt complications, and provide a literature review. Shunt complications related to pre-existing breast implants comprise nearly half of the breast-related shunt complications reported thus far. We present a complication of shunt failure in a 61-year-old woman who had previously undergone mastectomies for breast cancer with implant reconstruction. Following shunting, she developed headaches, fever, and right-sided breast swelling and erythma consequent to breast implant rupture, distal shunt migration, and CSF pseudocyst. This case is unique in that it involved rupture of a breast implant from VP shunt insertion. For complication avoidance, neurosurgeons should be aware of the potential pitfalls in shunting patients with breast implants.

Utility of daily image guidance with intensity-modulated radiotherapy for tumors of the base of skull.

BACKGROUND: This study was carried out to report our experience using intensity-modulated radiotherapy (IMRT) with daily image-guided radiotherapy (IGRT) for tumors involving the base of skull. METHODS: In all, 100 patients were prospectively treated with IMRT to a median dose of 64 Gy (range, 45-70 Gy). Daily helical megavoltage computed tomography (MVCT) scans were obtained as part of an IGRT registration protocol for patient alignment. RESULTS: The 2-year local-regional control was 91%. A total of 3295 daily MVCT scans were obtained. The mean shift to account for interfraction motion was 1.18 ± 1.75 mm, 1.81 ± 1.34 mm, and 1.33 ± 1.19 mm for the medial-lateral (ML), superior-inferior (SI), and anterior-posterior (AP) directions, respectively. Pretreatment shifts of >3 mm occurred in 10%, 26%, and 18%, in the ML, SI, and AP directions, respectively. CONCLUSIONS: The feasibility and efficacy of daily IGRT as a complement to IMRT for skull base were demonstrated.

Skull base surgery for the management of deeply invasive scalp cancer.

Skin cancer involving the scalp is a common malignancy in the "sun belt areas of the United States." Most early lesions are well managed by primary care physicians and dermatologists. Occasionally we encounter basal cell, squamous cell, and rarely Merkel cell carcinomas that have failed local therapy and present with large tumors invading full thickness scalp, calvarium, and even underlying dura. We describe our experience with 52 such tumors and illustrate their resections and reconstruction. For full thickness lesions we generally do a wide field resection of skin and underlying calvarium followed by dural resection. Reconstruction is usually with dural replacement, calvarial reconstruction with titanium mesh, and cutaneous reconstruction with a musculocutaneous free flap or muscular free flap with an overlying skin graft. Complications, survival rates, and recurrence rates will be presented.

New insights into the relationship between suture closure and craniofacial dysmorphology in sagittal nonsyndromic craniosynostosis.

Premature closure of the sagittal suture occurs as an isolated (nonsyndromic) birth defect or as a syndromic anomaly in combination with other congenital dysmorphologies. The genetic causes of sagittal nonsyndromic craniosynostosis (NSC) remain unknown. Although variation of the dysmorphic (scaphocephaly) skull shape of sagittal NSC cases has been acknowledged, this variation has not been quantitatively studied three-dimensionally (3D). We have analyzed the computed tomography skull images of 43 infants (aged 0.9-9 months) with sagittal NSC using anatomical landmarks and semilandmarks to quantify and characterize the within-sample phenotypic variation. Suture closure patterns were defined by dividing the sagittal suture into three sections (anterior, central, posterior) and coding each section as 'closed' or 'fused'. Principal components analysis of the Procrustes shape coordinates representing the skull shape of 43 cases of NSC did not separate individuals by sex, chronological age, or dental stages of the deciduous maxillary first molar. However, analysis of suture closure pattern allowed separation of these data. The central section of the sagittal suture appears to be the first to fuse. Then, at least two different developmental paths towards complete fusion of the sagittal suture exist; either the anterior section or the posterior section is the second to fuse. Results indicate that according to the sequence of sagittal suture closure patterns, different craniofacial complex shapes are observed. The relationship between craniofacial shape and suture closure indicates not only which suture fused prematurely (in our case the sagittal suture), but also the pattern of the suture closure. Whether these patterns indicate differences in etiology cannot be determined with our data and requires analysis of longitudinal data, most appropriately of animal models where prenatal conditions can be monitored.

Posttraumatic vasospasm detected by continuous brain tissue oxygen monitoring: treatment with intraarterial verapamil and balloon angioplasty.

INTRODUCTION: Posttraumatic vasospasm (PTV) is a relatively common event following traumatic brain injury (TBI) that has been strongly correlated with worse neurological outcome in many studies. However, vasospasm continues to be an under-recognized source of secondary injury following TBI, and currently published guidelines do not address screening or management strategies for PTV. Brain tissue oxygen (P(bt)O(2)) monitoring probes allow for continuous screening for cerebral hypoxia following TBI, but their use as a monitor for PTV has not been previously described. METHODS: Case report and literature review. RESULTS: We present a case of PTV identified by persistent low P(bt)O(2) despite aggressive medical therapy. Computed tomography and digital subtraction angiography confirmed severe cerebral arterial vasospasm involving both anterior and posterior circulations. The patient was successfully treated with serial intraarterial therapy including balloon angioplasty and verapamil infusion. CONCLUSION: Posttraumatic vasospasm should be included in the differential diagnosis of cerebral hypoxia (e.g., low P(bt)O(2)) following TBI. Management strategies for PTV may include early, aggressive intraarterial therapies including drug infusion and balloon angioplasty.

The option of Linac-based radiosurgery in a Gamma Knife radiosurgery center.

OBJECTIVE: Due to the fundamental differences in treatment delivery, linear-accelerator-based radiosurgery can be complementary to Gamma Knife (GK) for intracranial lesions. We reviewed the effect of adding GK to an existing linear accelerator (Linac)-based radiosurgery practice and analyzed case selections for the two modalities. PATIENTS AND METHODS: UC Davis Medical Center installed a Leksell Gamma Knife Model C in October 2003 to supplement an established Linac-based radiosurgery program. Radiosurgery indications for the 15 months before and after installation were compared. RESULTS: Radiosurgery cases expanded by twofold from 68 patients before GK installation to 139 after, with 106 treated by GK and 33 by Linac. Besides a major increase for trigeminal neuralgia and a general growth for acoustic neuroma, meningioma and brain metastases, case numbers for glioma and arteriovenous malformation (AVM) remained stable. Considering case selections for Linac, glioma decreased from 28 to 18%, while meningioma and metastases increased from 9 to 21% and 38-46%, respectively. The Linac patients receiving fractionated treatment also increased from 37 to 61%. CONCLUSIONS: While the majority of patients were treated with GK, a significant proportion was judged to be suited for Linac treatment. This latter group included particularly patients who benefit from fractionated therapy.

Secondary supratentorial primitive neuroectodermal tumor following irradiation in a patient with low-grade astrocytoma.

We report a case of a supratentorial primitive neuroectodermal tumor (PNET) that occurred 12 years after cranial irradiation for a grade II astrocytoma. Neuroimaging was unable to distinguish between a recurrence of the original neoplasm and the development of a new, distinct entity. Pathologic review assisted by immunohistochemical staining, however, revealed a high-grade PNET. Although rare, PNET needs to be included in the differential diagnoses for previously irradiated patients, who develop recurrent brain tumors in the presence of uncharacteristic imaging features.

Spontaneous epidural hemorrhage in chronic renal failure. A case report and review.

Spontaneous epidural hemorrhage has been described in a variety of clinical scenarios, including chronic renal failure (CRF). During hemodialysis, patients with CRF rarely develop spinal or cranial epidural hematomas. Such hemorrhages have been attributed to intracranial pressure fluctuations during hemodialysis, heparin administration, uremic-platelet syndrome, or hypertension. Although the exact pathophysiology is not understood, this rare consequence of hemodialysis has been well documented in the literature. Hemorrhage in the absence of hemodialysis therapy in a CRF patient, however, has not been previously reported. We report a 16-year-old boy with no history of trauma who woke in the morning with severe headache and resultant neurological deterioration. He was found to have a large left temperoparietal epidural hematoma and underwent urgent surgical evacuation. Postoperatively he developed a contralateral extra-axial hematoma that did not require surgical intervention. He recovered completely, with no significant neurological deficit. This unique presentation of spontaneous intracranial epidural hemorrhage in an adolescent not receiving hemodialysis highlights a rare, but serious, complication of CRF.

Giant juvenile nasopharyngeal angiofibroma: management by skull-base surgery.

From 1977 to 2001, 5 patients were seen with giant angiofibromas that had intracranial penetration. Three of these had involvement of the cavernous sinus with angiographic evidence of significant blood supply to the tumor. We attempted complete tumor removal in all patients via a skull-base procedure. The infratemporal fossa/middle fossa approach was used in 3 patients, an anterior craniofacial approach in 1, and an anterior subcranial approach in 1. Complete tumor removal was achieved in 4 patients and incomplete excision in 1. The latter was attempted with an anterior subcranial approach but required an infratemporal fossa/middle fossa approach for completion because of unanticipated cavernous sinus involvement. The patient declined further surgery. This was the only patient who had persistent disease. Preoperative and intraoperative management, blood loss, complications, and residual effects are described.

Assessment of proton microbeam analysis of 11B for quantitative microdistribution analysis of boronated neutron capture agents in biological tissues.

The (11)B(p,alpha)(8)Be* nuclear reaction was assessed for its ability to quantitatively map the in vivo subcellular distribution of boron within gliosarcomas treated with a boronated neutron capture therapy agent. Intracranial 9L gliosarcomas were produced in Fischer 344 rats. Fourteen days later, the majority of the rats were treated with f-boronophenylalanine and killed humanely 30 or 180 min after intravenous injection. Freeze-dried tumor cryosections were imaged using the (11)B(p,alpha)(8)Be* nuclear reaction and proton microbeams obtained from the nuclear microprobe at Lawrence Livermore National Laboratory. The (11)B distributions within cells could be imaged quantitatively with spatial resolutions down to 1.5 microm, minimum detection limits of 0.8 mg/kg, and acquisition times of several hours. These capabilities offer advantages over alpha-particle track autoradiography, electron energy loss spectroscopy, and secondary ion mass spectrometry (SIMS) for quantification of (11)B in tissues. However, the spatial resolution, multi-isotope capability, and analysis times achieved with SIMS are superior to those achieved with (11)B(p,alpha)(8)Be* analysis. When accuracy in quantification is crucial, the (11)B(p,alpha)(8)Be* reaction is well suited for assessing the microdistribution of (11)B. Otherwise, SIMS may well be better suited to image the microdistribution of boron associated with neutron capture therapy agents in biological tissues.

Syntheses and preliminary biological studies of four meso-Tetra[(nido-carboranylmethyl)phenyl]porphyrins.

Two meso-tetra[(nido-carboranylmethyl)phenyl]porphyrins (para- and meta-regioisomers) and their corresponding Zn(II) complexes have been synthesized with the aim of studying the effect of carborane distribution and metalation on the biological properties of this series of compounds. In vitro cell toxicity, uptake/efflux, and subcellular localization using rat 9L, mouse B16 and/or human U-373MG cells were evaluated. All four amphiphilic porphyrins display very low cytotoxicities and time- and concentration-dependent uptake by cells, which is influenced by serum proteins. Preliminary subcellular localization studies suggest that one of these compounds localizes in close proximity to the cell nucleus. All four nido-carboranylporphyrins show promise as boron-carriers for the boron neutron capture therapy of cancers, particularly the metal-free nido-carboranylporphyrins 5 and 12, which are able to deliver higher amount of boron to cells in vitro than the corresponding zinc complexes.